Sepsis and acute kidney injury (AKI) can account for up to 37% (Vincent et al.) and 39% (Fonseca Ruiz et al.) of critically ill patients hospitalized in intensive care units (ICU), respectively, and therefore represent major health challenges. Despite extensive research and recent advances in supportive care and diagnostic tools (Lever A; Reinhart K et al.), severe sepsis and septic shock remain associated with unacceptably high mortality rates (25-70%). In this context, AKI is a frequent (Klenzak; Rangel-Frausto M S et al.) and important complication of sepsis in critically ill patients (Mehta et al.), leading to an especially high mortality rate (Russell et al., 2000).
Different mouse models for sepsis have been developed, either to study the pathophysiology or to function as a preliminary testing ground. Injection of endotoxin (LPS), infection with exogenous bacteria and disruption of the host-barrier as in cecal ligation and puncture (CLP) or colon ascendens stent peritonitis (CASP), are among the most commonly studied mouse models for sepsis. Their representativeness for human sepsis has intensively been discussed (Buras et al., 2005; Rittirsch et al., 2007; Dyson and Singer, 2009). In general, clinically relevant sepsis models should incorporate a focus of infection as septic origin (Deitch, 1998). Although consecutive surgical focus sanitation is the most important therapeutic principle in humans, removal of the source of infection in CLP and CASP models to study recovery of sepsis-induced AKI is seldom reported (Maier et al., 2004; Hubbard et al., 2005; reviewed in Zanotti-Cavazzoni, 2009).
A need for better preclinical animal models of acute renal failure was expressed in the Second International Consensus Conference of the Acute Dialysis and Quality Initiative Group (Bellomo et al., 2004). Indeed, sepsis models often have difficulties in reproducing AKI since they are either too aggressive with consequent death or the insult is too mild to cause AKI (Barrera et al., 2010; reviewed in Doi et al., 2009 and Langenberg et al., 2008). In addition, supportive therapy, comorbidities and the effect of age are rarely included in those models, despite the fact that these aspects are of major clinical relevance for human sepsis (Dejager et al., 2011). Recently, a few complex extensions of the current animal models of human sepsis including aged mice or mice with pre-existing renal dysfunction (two-hit models) have been described as useful for detection of potential therapeutic targets (Doi et al., 2009; Fink, 2008; Holly et al., 2006; Miyaji et al., 2003). Importantly, these adapted models lead to increased reproducibility of AKI and provided additional insights into septic AKI mechanisms.
In addition to a need for better preclinical animal models, there is further an urgent need for early prediction, prognosis and/or diagnosis of sepsis, of AKI and, more specifically, of sepsis-induced AKI. Indeed, early and specific diagnosis of AKI is of benefit for the prevention and targeted intervention of sepsis-induced AKI (Soni et al., 2009). Recently, several promising biomarkers for AKI have been identified (e.g., IL-18, NGAL, KIM-1, CysC, L-FABP) and validated in clinical settings, yet few clinical studies have included septic patients (reviewed in Bagshaw et al., 2007). Although some of these biomarkers hold promise for real-time indication, early prediction or prognostic information of AKI (Haase et al., 2011; Devarajan, 2010), their specificity for diagnosis of sepsis-induced AKI still requires further study (Siew et al., 2009; Martensson et al., 2010; Nejat et al., 2010; Siew et al., 2010; Doi et al., 2010).
AKI may be due to other causes than sepsis. Indeed, it has been shown that in adults who underwent cardiac surgery, about 35% of patients developed AKI. Other risks for AKI include critical illness, circulatory shock, burns, trauma, major noncardiac surgery, nephrotoxic drugs or radiocontrast agents . . . (KDIGO consortium, Kidney International supplement 2, 2012). This KDIGO statement confirms the urgent need for early detection, prognosis and/or diagnosis of AKI due to any cause.
Chitinases and chitinase 3-like (CHI3L) proteins are members of the mammalian chitinase family (reviewed in Lee et al., 2011). CHI3L3 is a mouse specific chitinase 3-like protein and is strongly related to the human CHI3L protein 1 with which it has considerable sequence homology (Jin et al., 1998; Guo et al., 2000).
Hattori et al. (2009) suggested that serum concentrations of CHI3L1 (YKL-40) in human septic patients might be useful for severity grading of renal failure. However, elevated serum concentrations of CHI3L1 have also been reported in humans with certain types of solid tumors (reviewed in Lee et al.; 2011) and with other inflammatory conditions, such as inflammatory bowel disease (Bernardi et al., 2003), liver fibrosis (Johansen et al., 2000) and cardiovascular disease (Rathcke et al., 2010). Therefore, increased serum concentrations of CHI3L1 lack specificity and cannot diagnose sepsis and/or renal failure when concomitant diseases are present.
Acidic mammalian chitinase (CHIA, ACMase) (Lee et al., 2011), another member of the chitinase family, and sepiapterine reductase (Ichinose et al. 1991, Biochem Biophys. Res. Comm. 183) have not been described in relation to sepsis and/or AKI.